Structure I shown below is a typical core structure for a large number of natural and synthetic 20-ketosteroids, with the standard IUPAC numbering system of the carbon positions 1 to 21 indicated. ##STR1##
These types of steroids, with varying substituents and bonding, have many well-known therapeutic uses, especially based upon their anti-inflammatory activity. It is often desirable to deliver such steroids topically using aerosol spray devices, such as metered dose inhalers (MDIs). MDIs are commonly used to deliver steroids, e.g., beclomethasone dipropionate, to the airways of patients via oral or nasal inhalation for the treatment of asthma and allergic rhinitis.
One common difficulty, however, in making products for delivering steroids has been that they are often chemically unstable in aerosol formulations and degrade during storage. A great deal of research has been directed at steroid degradation. Chemical degradation is especially problematic when the steroid is dissolved in the formulation and, consequently, the vast majority of marketed MDI steroid products are formulated as particulate suspensions of the steroid, which are much less susceptible to chemical degradation than solutions. For example, it is believed that all currently marketed CFC-containing MDI products for delivering steroids are available only as particulate suspension formulations in CFC propellants.
More recently, some selected steroids have been reformulated as solutions in non-CFC hydrofluorocarbon (HFC) propellants with ethanol. In the case of beclomethasone dipropionate, for example, solution formulations are disclosed in U.S. Pat. No. 5,766,573 which are surprisingly chemically stable in propellant HFC 134a and/or 227 and ethanol in a conventional aluminum canister. Likewise, ciclesonide formulations are surprisingly chemically stable in certain solution MDI formulations disclosed in WO 98/52542. Solution formulations of flunisolide are disclosed in U.S. Pat. No. 5,776,433, where it is indicated that chemical stability may be enhanced by using additives like water, sorbitan trioleate, and cetylpyridinium chloride, and also that certain containers such as glass and resin coated aluminum enhance chemical stability and/or minimize the absorption of flunisolide onto the container wall. Also, WO 96/40042 discloses that aqueous formulations of triamcinolone acetonide in neutral or basic solutions undergo oxidative degradation catalyzed by trace levels of metal ions, especially copper, and proposes the use of EDTA as sequestering agent and/or adjusting pH.
Despite these limited examples, though, most commercial MDI formulations of steroids and other drugs have continued to be particulate suspensions. WO 98/13031, for example, discloses recent work on reformulating budesonide as a non-CFC suspension formulation. However, suspension formulations of a medicament are more likely to encounter problems with physical instability (e.g., agglomeration, crystal growth and deposition on the container wall, all resulting in inconsistent dosage delivery).
A drug delivery device providing medicinal steroid solution formulations with enhanced chemical stability would offer some significant advantages over suspension formulations. Besides homogeneity, solution formulations have been found in some cases--e.g., using HFC propellants and low ethanol content--to give dramatically higher respirable fractions (i.e., the percentage of active ingredient able to reach the airways of the lung) compared to a particulate suspension of the steroid drug. See U.S. Pat. No. 5,776,432. Furthermore, an aerosol product providing a chemically and physically stable aerosol steroid formulation using non-CFC propellant would offer the advantage of being more ozone friendly than currently available aerosol products with CFCs.
Nevertheless, despite a substantial need, the problem of chemical degradation in steroid solution aerosol products has been poorly understood. Until now there has been no way to identify which steroids are likely to be most stable as solution aerosols and which will be most sensitive to degradation in solution aerosol products or how to reduce such degradation.